Familial Hyperkalemic Periodic Paralysis Caused by a De Novo Mutation in the Sodium Channel Gene SCN4A

Case report http://dx.doi.org/10.3345/kjp.2011.54.11.470 Korean J Pediatr 2011;54(11):470-472

Familial hyperkalemic periodic paralysis caused by a de novo mutation in the sodium channel gene SCN4A

Ji-Yeon Han, MD, June-Bum Kim, MD, PhD Familial hyperkalemic periodic paralysis (HYPP) is an autosomal- dominant channelopathy characterized by transient and recurrent Department of Pediatrics, Konyang University College episodes of paralysis with concomitant hyperkalemia. Mutations in the of Medicine, Daejeon, Korea skeletal muscle voltage-gated sodium channel gene SCN4A have been reported to be responsible for this disease. Here, we report the case of a 16-year-old girl with HYPP whose mutational analysis revealed a heterozygous c.2111C>T substitution in the SCN4A gene leading to a Thr704Met mutation in the protein sequence. The parents were clini­ cally unaffected and did not have a mutation in the SCN4A gene. A de novo SCN4A mutation for familial HYPP has not previously been Received: 5 April 2011, Revised: 7 June 2011 reported. The patient did not respond to acetazolamide, but showed Accepted: 6 July 2011 Corresponding author: June-Bum Kim, MD, PhD a marked improvement in paralytic symptoms upon treatment with Department of Pediatrics, Konyang University College of hydrochlorothiazide. The findings in this case indicate that ade novo Medicine, 685 Gasuwon-dong, Seo-gu, Daejeon 302-718, Korea mutation needs to be considered when an isolated family member is Tel: +82-42-600-9230, Fax: +82-42-600-8835 found to have a HYPP phenotype. E-mail: [email protected]

Copyright © 2011 by The Korean Pediatric Society Key words: Hyperkalemic periodic paralysis, Mutation, SCN4A This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by- nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction in HYPP. Described here is a case of HYPP in a patient with an ap­ parently sporadic presentation who carries a de novo mutation in the Familial hyperkalemic periodic paralysis (HYPP, online mendelian SCN4A gene. This mutation predicts a codon change from threonine inheritance in man [OMIM] no. 170500) is an autosomal-dominant to methionine at residue 704 (Thr704Met, c. 2111C>T). This is the pathology of the sodium channels that results in reversible flaccid first report describing a spontaneous mutation in theSCN4A gene in paralysis with episodic hyperkalemia1). The symptoms usually begin a patient with HYPP whose parents neither possessed nor transmitted in the first decade of life, presenting as bouts of mild-to-severe muscle the same mutation. weakness lasting for minutes to hours. The paralytic attacks occur most frequently in the morning and are commonly triggered or ag­ Case report gravated by fasting, potassium-rich foods, emotional stress, or rest after vigorous exercise1,2). Mutations in the SCN4A gene (OMIM no. A 16-year-old girl was referred to our clinic for evaluation of periodic 603967), which encodes the alpha subunit of the skeletal muscle so­ muscle weakness experienced over the past 7 years. During the early dium channel, are responsible for the majority of HYPP cases3). stages, her paralytic attacks occurred at a frequency of once a month, To our knowledge, de novo mutations have not yet been reported but recently, they occurred 2 or 3 times a week, and generally lasted

470 Korean J Pediatr 2011;54(11):470-472 • http://dx.doi.org/10.3345/kjp.2011.54.11.470 471 from at least a few minutes up to 3 hours. The muscle weakness was consent, and the study was conducted in compliance with the Institu­ often generalized. Acute crises often followed the ingestion of orange tional Review Board of Konyang University Hospital. juice or watermelon, stressful circumstances, fatigue, and oversleeping. Direct sequencing of SCN4A exon 13 revealed a heterozygous C>T Her parents were clinically unaffected (Fig. 1A) and had never transition at nucleotide 2111 (Fig. 1B), resulting in the substitution of experienced paralytic symptoms. a threonine by a methionine at codon 704 (Thr704Met). This mutation At admission, she exhibited no abnormal symptoms following was absent in the patient’s parents (Fig. 1B). Parental identity was physical examination, electrocardiography, and radiological investiga­ verified by genotyping 15 short tandem repeat markers by using a tion. She had no abnormal findings in laboratory testing (e.g., blood PowerPlex 16 system (Promega, Madison, WI, USA). urea nitrogen, 8.4 mg/dL; creatinine, 0.75 mg/dL; Na, 138 mmol/

L; K, 4.4 mmol/L; HCO3, 24.5 mmol/L; and Urine, PH 6.0), except Discussion for an increased level of serum creatine kinase (621 IU/L; normal range, 32 to 294 IU/L). There was no grip or percussion myotonia. SCN4A mutations are associated with various neuromuscular Paramyotonic symptoms, such as muscle stiffness and eyelid lag, disorders, including HYPP, normokalemic periodic paralysis, hypo­ were not induced by exposure to cold. Holter monitoring for 24 kalemic periodic paralysis, paramyotonia congenita, potassium-ag­gra­ hours did not reveal any structural abnormalities. In order to induce vated myotonia, and congenital myasthenic syndrome3,6). Despite paralytic symptoms, we administered oral potassium chloride (2.4 g), after which the patient developed paresthesias in both hands after 20 minutes, followed by severe flaccid paralysis of all 4 limbs, with a rating of 1 according to the Medical Research Council scale4). Sensory examination revealed no deficits. Deep tendon reflexes were absent in all limbs, and Babinski and Hoffmann signs were not present. Cognitive and autonomic functions were preserved. No clinical or electrical myotonia was present. During the attack of muscle weakness, the patient showed increased levels of serum potassium (6.5 mEq/L; normal range, 3.5 to 5.0 mEq/L) and creatine kinase (854 IU/L), with the electrocardiograms showing characteristically tall and peaked T waves. Thirty minutes after intravenous injection of glucose and insulin, serum potassium concentrations decreased to 4.2 mEq/L, and both the clinical manifestations and electrocardiographic measure­ ments returned to normal. Initial empirical treatment with acetazolamide (starting at 250 mg twice daily) was administered to the patient, who was also advised to avoid potassium-rich foods, fasting, and strenuous exercise. Prophy­ lactic treatment with acetazolamide was ineffective, however, and the patient was consequently prescribed hydrochlorothiazide (25 mg twice daily). The frequency and severity of paralytic attacks were markedly reduced after administration of this medication. We have been regularly monitoring the serum electrolyte values, including Na, K, and chloride, on an outpatient basis since the patient was discharged from the hospital. The electrolyte levels have remained within normal ranges (e.g., K, 3.7 to 5.0 mEq/L; Na, 136 to 140 mEq/L). Mutation screening was performed by sequence analysis of the Fig. 1. Family pedigree and mutation analysis. (A) Pedigree of the hyper­ entire coding region of the SCN4A gene as has been previously des­ kalemic periodic paralysis (HYPP) patient shows the proband (indicated 5) by an arrow). (B) Identification of a de novo mutation in the SCN4A gene cribed . Genomic DNA was extracted from the peripheral blood in the HYPP patient. Electropherograms show the sequence encompassing of the patient and her parents with a DNA extraction kit (SolGent, the heterozygous transition mutation (c.2111C>T) in exon 13 of SCN4A in the patient as well as the corresponding wild-type sequences in normal Daejeon, Korea). All participants provided their written informed family members. 472 JY Han and JB Kim • De Novo SCN4A Mutation in HYPP some overlapping characteristics between these diseases, clinicians References have attempted to differentiate between them mainly because the therapeutic response to medications is somewhat different7). In the 1. Lehmann-Horn F, Rudel R, Jurkat-Rott K. Non-dystrophic myotonias present study, DNA sequence analysis of the SCN4A gene revealed a and periodic paralyses. In: Engel A, Franzini-Armstrong C, editors. Myo­ logy: basic and clinical. 3rd ed. New York: McGraw-Hill, 2004:1257-300. de novo Thr704Met mutation in a single member of a family whose 2. Feero WG, Wang J, Barany F, Zhou J, Todorovic SM, Conwit R, et parents were clinically unaffected and did not show a mutation in al. Hyperkalemic periodic paralysis: rapid molecular diagnosis and the SCN4A gene. De novo mutations have not previously been relationship of genotype to phenotype in 12 families. Neurology 1993; reported in HYPP. We think that the reason for this rarity of de novo 43:668-73. mutations in HYPP, unlike in other autosomal-dominant channelo­ 3. Jurkat-Rott K, Lehmann-Horn F. Genotype-phenotype correlation and therapeutic rationale in hyperkalemic periodic paralysis. Neurotherapeutics pathies, is either the low incidence per se or the clinical variability 2007;4:216-24. of this disease. Previous studies have revealed that certain SCN4A 4. Paternostro-Sluga T, Grim-Stieger M, Posch M, Schuhfried O, Vacariu mutations in HYPP exhibit phenotypic variations8-10). Phenotypic G, Mittermaier C, et al. Reliability and validity of the Medical Research variability may disturb the correlation between genotype and Council (MRC) scale and a modified scale for testing muscle strength in patients with radial palsy. J Rehabil Med 2008;40:665-71. phenotype in HYPP, making it difficult to differentiate the disease 5. Park YH, Kim JB. An atypical phenotype of hypokalemic periodic paralysis from other allelic ion channel pathologies, including paramyotonia caused by a mutation in the sodium channel gene SCN4A. Korean J congenita, normokalemic periodic paralysis, and potassium-aggravated Pediatr 2010;53:909-12. myotonia. The patient in this case exhibited only flaccid muscle 6. Hantaï D, Richard P, Koenig J, Eymard B. Congenital myasthenic synd­ romes. Curr Opin Neurol 2004;17:539-51. weakness without (para)myotonia, which the authors termed “pure 7. Ricker K, Böhlen R, Rohkamm R. Different effectiveness of tocainide HYPP”. A case of pure HYPP with Thr704Met mutation has not and hydrochlorothiazide in paramyotonia congenita with hyperkalemic previously been reported in Asia. episodic paralysis. Neurology 1983;33:1615-8. Prophylactic use of acetazolamide has been considered to be highly 8. Brancati F, Valente EM, Davies NP, Sarkozy A, Sweeney MG, LoMonaco M, effective for treating patients with periodic paralyses11-13). Non­etheless, et al. Severe infantile hyperkalaemic periodic paralysis and paramyotonia congenita: broadening the clinical spectrum associated with the T704M some patients with specific mutations reported no effect and even mutation in SCN4A. J Neurol Neurosurg Psychiatry 2003;74:1339-41. worsening of paralytic symptoms after acetazolamide treatment14,15). 9. Bouhours M, Luce S, Sternberg D, Willer JC, Fontaine B, Tabti N. Thiazide diuretics have been used as alternatives to acetazolamide A1152D mutation of the Na+ channel causes paramyotonia congenita in cases where initial empirical therapy with acetazolamide was and emphasizes the role of DIII/S4-S5 linker in fast inactivation. J Physiol 2005;565(Pt 2):415-27. ineffective. In the present study, the patient who was unresponsive to 10. Okuda S, Kanda F, Nishimoto K, Sasaki R, Chihara K. Hyperkalemic acetazolamide reported a marked decrease in the frequency and intensity periodic paralysis and paramyotonia congenita--a novel sodium channel of paralytic attacks after treatment with hydrochlorothiazide. It remains mutation. J Neurol 2001;248:1003-4. to be elucidated whether the improvement of paralytic symptoms in 11. Lehmann-Horn F, Jurkat-Rott K. Voltage-gated ion channels and hereditary our patient is associated with genetic or allelic variations in response to disease. Physiol Rev 1999;79:1317-72. medications. 12. Lehmann-Horn F, Rüdel R. Molecular pathophysiology of voltage-gated ion channels. Rev Physiol Biochem Pharmacol 1996;128:195-268. In conclusion, we reported the first de novo SCN4A mutation in 13. Ptácek L. The familial periodic paralyses and nondystrophic myotonias. a patient with HYPP whose parents were clinically and genetically unaf­ Am J Med 1998;105:58-70. fected. Our findings have implications for the diagnosis and genetic 14. Miller TM, Dias da Silva MR, Miller HA, Kwiecinski H, Mendell JR, Tawil counseling of an isolated family member who has phenotypic features R, et al. Correlating phenotype and genotype in the periodic paralyses. of HYPP. These results also suggest thatde novo SCN4A mutations Neurology 2004;63:1647-55. in this disorder may occur more frequently than might previously 15. Kim JB, Kim MH, Lee SJ, Kim DJ, Lee BC. The Genotype and clinical phenotype of Korean patients with familial hypokalemic periodic paralysis. J have been anticipated. Korean Med Sci 2007;22:946-51.

Acknowledgement

This work was supported by the Korea Research Foundation Grant funded by the Korean Government (MOEHRD, Basic Research Promotion Fund) (KRF-2008-331- E00158).